Protozoan parasites such as Plasmodium falciparum and Toxoplasma gondii belong to the phylum of Apicomplexa and the class of Coccidia.
Coccidia are among the most important parasites of animals parasites and some are human pathogens of major medical importance: the causative agent of malaria, Plasmodium falciparum, causes death of more than two million children every year while other Apicomplexa such as Toxoplasma gondii and to a lesser extent Cryptosporidium parvum are devastating human pathogens when they parasitize immunocompromised hosts.
As to Toxoplasma gondii, following an asymptomatic parasitic process caused by the tachyzoite stage (replicative stage) but efficiently controlled by the host immune system, the parasite may persist as cryptic, <<dormant >> bradyzoite stage within intracellular cysts. These cysts resulting from host and parasite factors preferentially develop in muscle and brain tissues. Though the mechanisms by which cysts persist in the brain are not well defined yet, it is clear that the immune cells and their associated cytokine production play a major role. When this subtle immune interplay is disrupted as it occurs in AIDS patients, it induces cyst reactivation which is accompanied by the parasite differentiation from the slow growing bradyzoite stage into a highly replicative tachyzoite stage responsible for infiltrated <<inflammatory>> foci that leads to encephalitis. Currently existing chemotherapeutic treatments, while effective at controlling the parasite are poorly tolerated particularly by immunocompromised individuals.
Toxoplasma infection may also be congenitally acquired. Such infection occurs only when a woman becomes primo-infected during pregnancy and severity of the disease may depend upon the stage of pregnancy at time of infection. Focal lesions develop in the placenta and the fetus may become infected. Apart from abortion, by far the most common sequel of congenital toxoplasmosis is ocular disease (blindness) but mental retardation is also quite common.
As such the identification of molecules or molecular complexes of parasite origin and involved in the survival of the parasite should remain a research priority since it could lead to more targeted treatments.
Certain developmental stages of these parasites including the sporozoites of Plasmodium, Cryptosporidium and Toxoplasma as well as the tachyzoites of Toxoplasma, move by a gliding motion across either a mucous layer or an extracellular matrix before encountering their host cells. They subsequently enter these cells by an active process and once in a suitable intracellular niche, they either multiply and/or differentiate, two steps required for parasite spreading before transmission to a new host.
The strategies selected by these parasites for either gliding onto a substratum or for invading their host cells depend on the dynamics of their actin cytoskeleton. However, unlike during the crawling motility of higher eucaryotes, the remodeling of actin cytoskeleton remains discrete and speed values of gliding zoïtes are an order of magnitude faster than for most specialized crawling cells. In addition, host cell invasion occurs within few seconds. These peculiar features prompted us to search for molecules underlying the formation of the motile force in tachyzoïtes of Toxoplasma gondii. The inventors have recently identified Toxofilin, a novel actin binding protein, as the major candidate for controlling actin dynamics in tachyzoïtes. Toxofilin has been purified in complex with parasite actin monomers and in vitro assays have demonstrated it regulates the competence of actin monomers to associate and of polymers to elongate. When Toxofilin was ectopically overexpressed as GFP-tagged protein in mammalian non-muscle cells it clearly disrupted the actin cytoskeleton and caused disassembly of actin stress fibers. In tachyzoites, Toxofilin binds G-actin and copurifies with a parasite F-actin containing fraction suggesting that it may control parasite actin dynamics as well. Such a role was further suggested by the highly variable localization pattern of Toxofilin in the moving parasite i.e. during gliding or host cell entry (see Poupel et al., 2000. Molecular Biology of the Cell, vol 11, pp 355-368).